R

t-Bu

(6a) R1 = OMe; R2 = OH agonist (6b) R1 = OH; R2 = OMe antagonist

(7) agonist

(7) agonist

(8) antagonist

(8) antagonist

In nonivamide and RTX derivatives, the antagonist activity depends on the location of iodine, with antagonism being maximal at C-5' in RTX (2b) and at C-6' in nonivamide (4b). Complementary iodination at C-5' in nonivamide (4c) could still reverse activity [68], but iodination of RTX at C-6' (2c) yielded only a partial agonist [72].

Detailed structure-activity studies on the effect of aromatic substitution were carried out with nonivamide (4a), a compound structurally simpler and more easily available than RTX [73]. While iodination at C-2' (4d) led to the loss of affinity for TRPV1, iodine was better than bromine or chlorine for the reversal of activity, both at C-5 and at C-6 . Within C-6 substituted nonivamides, iodine was also better than alkyl (alkenyl, alkynyl) groups for the reversal of activity. Finally, comparison of potency among a series of agonist capsaicinoids and their corresponding 6 -iodinated antagonists showed a poor correlation. For example, 6 -iodophenylacetylrinvanil (PhAR, 9b) showed very potent antagonist activity (IC50 = 6 nM), in keeping with the agonist ultrapotency of phenylacetylrinvanyl (PhAR, 9a) [74]. In contrast, olvanil (10a) and arvanil (11a), both more potent agonists than nonivamide [75], yielded 6'-iododerivatives (compounds 10b and 11b, respectively) less potent as antagonists than 6 -iodononivamide, and retvanil

0 0

Post a comment